Targeting Replication Stress in Pediatric and AYA Osteosarcoma
Abstract
Osteosarcoma (OS) is the most common bone cancer in children as well as in adolescents and young adults (AYA). In OS, treatment has not improved in the past 3 decades, underscoring the urgency for developing efficacious and safe therapies. While front-line chemotherapy increases patient survival to some extent, 25-50% of the patients already have metastatic disease at the time of diagnosis and remain challenging to treat. This is due, in part, to changes in gene composition in the OS cells called copy number variations (CNVs) which lead to drastic changes proteins resulting in uncontrolled cancer cell growth. In normal cells, two copies of each gene exist. As cancer cells continue to grow, CNVs emerge resulting in increased copies or deletions of genes that ultimately lead to increased proliferation, survival and metastasis of OS cancer cells. Our long-term objective is to improve therapeutic outcomes in OS by designing safe combination therapies based on the mutational profile of the OS tumors. Our proposed research aligns with the Overarching Challenge (Section II.A.3) to advance treatment strategies and outcomes in both military and civilian populations encompassing communities of color and women. Information gained here will provide strong translational rationale for targeting RS and moving this approach forward for clinical testing in aggressive and metastatic OS. Our team previously used comprehensive patient datasets to discover CNVs that are indicators of abnormal growth in OS. We were particularly interested in identification of CNVs that provide clues to what is dysregulated in the OS cells but also have drugs already studied in the clinic that we can safely combine to block the dysregulation. Our rationale was that this would greatly speed up the time that a combination of drugs could be tested in a clinical trial setting. Analysis of pediatric and AYA OS CNVs from public and Riley Hospital for Children databases identified a large number of CNVs associated with poor overall survival in OS patients. As mentioned above, these CNVs were then linked to drugs that are being tested in other cancers and can be used to target the CNV-associated abnormal growth in OS patients. Indeed, analysis of pediatric and AYA OS CNVs indicated that genes involved in the abnormal growth process in OS called replication stress (RS) were found to be duplicated or amplified in OS patients predicted to have a poor outcome and not survive. In OS patients harboring increased copies of genes associated with RS such as MYC and RAD21, this correlated with poor overall survival (n=85 patients analyzed). The dysregulated process of RS can be exploited by using drugs that will uncouple RS in the cancer cells from strategies that the cancer cells typically use to survive. In this proposal, our strategy is to focus on two types of drugs that inhibit critical regulators of replication stress called bromodomain and extraterminal (BET) proteins and CHK1. Our preliminary data in clinically relevant pediatric and AYA mouse models of OS indicated that a combination therapy of inhibitory drugs to BETs and CHK1 is well tolerated and significantly blocks human OS tumor growth. Based on these data, our objective is now to use a diverse panel of OS models developed and characterized by our team that include relevant biological variables such as ethnicity, gender, and age. New information critical to moving this approach to the clinic will be obtained. We will gain a detailed understanding of how BET and CHK1 inhibition can kill OS cells and discover how some of the OS cells may adapt to therapy and become more resistant to therapy. We will also learn how to best use BET and CHK1 inhibitors in combination with chemotherapy used to treat OS once it recurs and metastasizes. Data obtained from studies is of high relevance to active-duty Service Members, Veterans, and other military beneficiaries. Information obtained through these studies will help inform dev
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210615
Entities
People
- Karen Pollok
Organizations
- Indiana University
- United States Army